DABCO-promoted one-pot synthesis of heteroaryl-substituted benzenes and their biological evaluation

Article abstract of DOI:10.1007/s00044-013-0857-0

A simple and efficient one-pot synthesis of heteroaryl-substituted benzenes has been developed via cyclocondensation of vinylmalononitriles and ethylvinylcyanoacetates with heteroarylnitroolefines using diazabicyclo[2,2,2] octane as catalyst. The titled compounds were evaluated for their antitubercular, antibacterial and antifungal activities at various concentrations. Springer Science+Business Media 2013.

Full text of DOI:10.1007/s00044-013-0857-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:2608–2614
DOI 10.1007/s00044-013-0857-0
ORIGINAL RESEARCH
DABCO-promoted one-pot synthesis of heteroaryl-substituted
benzenes and their biological evaluation
•
G. Neelaiah Babu Haile Micheal Ayalew
•
Shubha Jain
Received: 18 June 2013 / Accepted: 17 October 2013 / Published online: 27 October 2013
Ó Springer Science+Business Media New York 2013
Abstract A simple and efficient one-pot synthesis of het-
eroaryl-substituted benzenes has been developed via cyclocon-
densation of vinylmalononitriles and ethylvinylcyanoacetates
with heteroarylnitroolefines using diazabicyclo[2,2,2]octane as
catalyst. The titled compounds were evaluated for their antitu-
bercular, antibacterial and antifungal activities at various
concentrations.
coupling reactions (Saito and Yamamoto, 2000) based on
the given aromatics are interpreted as traditional approa-
ches. On the other hand, the approach to construct aromatic
backbone from catenulate precursors has received growing
interest not only due to the short sequence and regiose-
lectivity, but also due to the advancement from the view
point of atom economy (Trost, 1991) and environmental
concern. These general features are common in the most
useful benzannulation reactions such as the [4?2] cyclo-
addition of metalacyclopentadienes and alkynes (Xi et al.,
2003), transition metal catalysed [4?2] cycloadditions
(Bonaga et al., 2005), [5?1] benzannulation strategy
between alkenoyl keteneacetals and nitro-alkane (Barun
et al., 2002), and [4?2] benzannulation of O-alkynyl
benzaldehyde and alkyne (Asao et al., 2003).
Keywords Heteroayl-substituted benzenes ꢀ DABCO ꢀ
Antitubercular activity ꢀ Antibacterial activity ꢀ
Antifungal activity
Introduction
Polysubstituted benzenes are highly useful compounds in
organic chemistry, natural product chemistry and pharma-
ceutical chemistry. Polysubstituted benzenes also play
important role in medicinal chemistry for the fact that they
have common structural features in various bioactive
molecules and are frequently employed as precursors for
the synthesis of many bioactive heterocyclic compounds
(Warshakoon et al., 2006). Consequently enormous num-
bers of procedures have been developed for the construc-
tion of polysubstituted benzenes. Aromatic substitutions
including Freidel–Crafts acylations and alkylations (Olah,
1963) nucleophilic substitutions (Hassan et al., 2002), and
In general, it is difficult to introduce a heteroaryl group,
nitrile and ester group to the given aromatics. Some methods
were developed to synthesise the functionalized benzenes
from acyclic compounds as follows: (i) Base-promoted cy-
clocondensation of arylethyldene and arylidene malono-
nitriles and the elimination of nitrile group in succession,
which provides 2-amino isophthalonitriles (Milart et al.,
1998). (ii) One-pot two-step tandem reaction of vinyl mal-
ononitriles and nitro olefins promoted by two different kinds
of bases for each step, which obtains a series of substituted
2-amino-3-nitro benzonitriles (Xue et al., 2007), and (iii)
one-pot synthesis of 2-amino-3-nitro-benzonitriles and
2-amino-3-nitro benzoates by the condensation of activated-
methylene alkenes with nitro olefins using Cu(OTf)2/Et3N
(Weike et al., 2009). But, these methods often suffer from
certain drawbacks such as long playing procedures, haz-
ardous by products, use of stoichiometric or even excess
amount of base and use of metal triflates. Therefore, to
synthesise poly substituted benzenes efficiently and cata-
lytically is an important task in organic synthesis.
G. N. Babu ꢀ S. Jain
School of Studies in Chemistry & Biochemistry, Vikram
University, Ujjain 456010, Madhya Pradesh, India
G. N. Babu (&) ꢀ H. M. Ayalew
Department of Chemistry, College of Natural and Computational
Sciences, Haramaya University, Dire Dawa, Ethiopia
e-mail: gnbabu24@gmail.com
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Med Chem Res (2014) 23:2608–2614
2609
Therefore, in continuation of our interest towards the
using of diazabicyclo-[2,2,2]-octane (DABCO) in various
organic syntheses (Jain et al., 2012a, 2013) herein we are
reporting a new synthetic method for the synthesis of
heteroaryl-substituted benzenes using vinylmalononitriles,
obtained from ketones via a Knoevenagel reaction with
heteroarylnitroolefins in the presence of DABCO as base
and CH3CN as the solvent via one-pot tandem addition
process. This introduces a new strategy for the synthesis of
heteroaryl-substituted aromatic compounds using heteroa-
rylnitroolefins as the starting materials.
(2 mmol) and CH3CN in different amounts of DABCO
(Table 1). The efficiency of the reaction is mainly affected
by the amount of the catalyst. No product could be detected
in the absence of the catalyst even after 12 h (entry 1), while
good results were obtained in the presence of DABCO. The
optimal amount of the catalyst was 5 mol% (entry 3), the
higher amount of the catalyst did not increase the yield
noticeably (entry 6).
In our initial study, we observed that vinyl malononitr-
iles 2(a–f) could undergo cyclocondensation with hetero-
arylnitroolefins 1(a–c) in the presence of 5 mol% of
DABCO (Scheme 1). The reaction was carried out under
air. Acetonitrile was chosen as solvent due to solubility of
all starting materials. The products, a series of 2-amino-3-
nitro-4-heteroarylbenzonitriles 4(a–f) are obtained in good
yields. The details are summarised in (Table 2).
Physical properties of DABCO
(a) Appearance solid
(b) Colour white
(c) Odour no specific
To extend the scope of the reaction, other activated
alkenes, such as Knoevenagel condensed products of
ketones with ethylcyanoacetate 3(a–f), were made to react
with heteroaryl nitroolefins 1(a–c) using the present pro-
tocol (Scheme 2). The products were obtained in moderate
yields. The details are summarised in Table 3.
(d) Melting range 156–159 °C
(e) Boiling range 174 °C
(f) Vapour pressure 3.9 hPa at 50 °C
(g) Relative density 1.02 g/mL at 25 °C
(h) Water solubility soluble
(i) Molecular formula C6H12N2
In order to show the merit of the present work in com-
parison with some reported protocols, we compared the
results of the synthesis of heteroaryl-substituted benzenes
in the presence of K2CO3, Cu(OTf)2/Et3N, EtONa, GIL
and Pyridine with DABCO with respect to the reaction
times and yield of the product (Table 4). However, reaction
Results and discussion
In order to optimise the reaction conditions, the synthesis of
compound 4c (Table 2) was used as a model reaction.
Therefore, the reaction was carried out by stirring a mixture
of vinyl malono nitrile 2 (2 mmol), heteroarylnitroolefin 1c
Table 2 DABCO-promoted synthesis of 2-amino-3-nitro-6-hetero-
arylbenzonitriles (4a–f)
Entry R1
X
DABCO
(mol%)
Time Product Yield M.p.
(%)a
(h)
(°C)
Table 1 Effect of different concentrations of catalyst for the syn-
thesis of heteroaryl-substituted benzenes
1
2
3
4
C6H5
NH 5
5
4a
4b
4c
4d
74
84
88
70
211–218
189–191
273–275
226–229
C6H5
C6H5
S
5
5
4.5
4
Entry Catalyst
Catalyst loading (mol%) Time (h) Yield (%)b
O
1
2
3
4
5
6
a
No catalyst
–
1
12a
7
–
4-OMe– NH 5
C6H4
4
DABCO
DABCO
DABCO
DABCO
DABCO
64
76
88
88
86
5
6
4-OMe–
C6H4
S
5
5
4e
4f
84
80
201–203
243–245
5
5
10
15
20
4
4-OMe–
C6H4
O
5
4.5
4
3.5
Vinyl malanonitrile (2 mmol), heteroarylnitroolefin (2 mmol) and
5 mol% DABCO in CH3CN under reflux temperature
No change observed even after prolonged stirring up to 12 h
Isolated yields
b
a
Isolated yields
Scheme 1 Synthesis of 2-amino-3-nitro-6-heteroarylbenzonitriles
(4a–f)
Scheme 2 Synthesis of ethyl-2-amino-3-nitro-4-heteroarylbenzoates
(5a–f)
123

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Med Chem Res (2014) 23:2608–2614
in the presence of these catalysts required longer reaction
times than DABCO.
heteroarylnitroolefins, the cyclisation catalysed by 5 mol%
DABCO, and the oxidation takes place in atmosphere to
form heteroaryl-substituted benzene.
Based on the experimental results, a plausible reaction
mechanism is illustrated (Scheme 3). The reaction involves
the Michael addition of activated alkenes with
The antitubercular data (Table 5) revealed that the
synthesised heteroaryl-substituted benzenes 4(a–c) and
5(d–f) proved to be active against Mycobacterium tubercu-
losis H37Rv strain at 100, 10 and 1 lg/mL levels. The anti-
bacterial data (Table 6) shows that the product 4a and 5e
displayed broad-spectrum activity, whereas 4c and 5d
showed moderate activityand 4band 5f showed poor activity
against tested bacteria. The antifungal data (Table 7) show
that the product 5e displayed broad-spectrum activity against
Candida tropicalis, 4a and 4b against Candida albicans and
4c and 5e against both Aspergillus flavus and C. albicans. It
is clear that compounds 5e and 4a–c possess high activity,
while rest of the products possesses moderate activity.
Table 3 DABCO-promoted synthesis of ethyl-2-amino-3-nitro-4-
heteroarylbenzoates (5a–f)
Entry R1
X
DABCO Time Product Yield M.p.
(mol%) (h)
(%)a (°C)
1
2
3
4
C6H5
NH 5
5.5
6
5a
5b
5c
5d
62
65
61
57
203–205
C6H5
C6H5
S
5
5
195–197
291–293
231–233
O
5
4-OMe–
C6H4
NH 5
5
5
6
4-OMe–
C6H4
S
5
5
5.5
5
5e
5f
64
68
213–215
257–259
4-OMe–
C6H4
O
Experimental
Ethylvinylcyanoacetate (2 mmol), heteroarylnitroolefin (2 mmol),
and 5 mol% DABCO in CH3CN under reflux temperature
General
a
Isolated yields
Melting points were measured on an Electro thermal 9100
apparatus and were uncorrected. All chemicals were pur-
chased from Merck and Fluka used without further purifi-
Table 4 Comparison of our results with earlier reported methods
1
Entry Catalyst
Conditions
Time (h) Yield (%)a,b
cation. H-NMR spectra were obtained on a Bruker DRX-
400 and 13C-NMR spectra on a Bruker DRX-125 Advance
spectrometer. FT-IR spectra were recorded on a Shimadzu
FT-IR-8400S spectrometer. Chemical shifts of 1H and
13C-NMR spectra were expressed in ppm in downfield
from tetramethylsilane. Antitubercular activity was tested
against M. tuberculosis H37Rv strain using Lowenstein–
Jensen medium method. Antibacterial and antifungal sus-
ceptibility test was done by disc diffusion method.
1
2
3
4
5
6
a
K2CO3
DMF/RT
16
6
67c
72d
78e
57f
63g
88h
Cu(OTf)2/Et3N DMF/reflux
EtONa
GIL
CH3CN/reflux
H2O/reflux
8
7
Pyridine
DABCO
MW/159W, 100 °C 10 min
CH3CN/reflux
4
Jain et al. (2012c)
Chen et al. (2011)
Kim et al. (2008)
Weike et al. (2009)
Xue et al. (2007)
Xin et al. (2010)
b
c
General procedure for the synthesis of 2-amino-3-nitro-
d
e
4-heteroarylbenzonitriles (4a–f)
f
To a mixture vinyl malononitrile 2 (2 mmol) and hetero-
arylnitroolefin 1 (2 mmol) in CH3CN (15 mL), DABCO
(5 mol%) was added. The reaction mixture was stirred at
reflux for 4 h. After completion of the reaction, EtOAc
g
h
Krishna and Satish (2010)
This work
Scheme 3 A plausible
mechanism for the preparation
of heteroaryl-substituted
benzene
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Med Chem Res (2014) 23:2608–2614
2611
(15 mL) was added to dilute the reaction solution. Then,
the mixture was washed with water and brine. The com-
bined organic phases were dried and concentrated under
vacuum, and the residue was purified by column chroma-
tography (hexanes: EtOAc) to afford compound 4.
added. The reaction mixture was stirred at reflux for 4 h.
After completion of the reaction, EtOAc (15 mL) was
added to dilute the reaction solution. Then, the reaction
mixture was washed with water and brine. The combined
organic phases were dried and concentrated under vacuum,
and the residue was purified by column chromatography
(hexanes: EtOAc) to afford compound 5.
General procedure for the synthesis of ethyl 2-amino-3-
nitro-4-heteroarylbenzoates (5a–f)
Microbiology
To a mixture of 3 (2 mmol) and heteroarylnitroolefin 1
(2 mmol) in CH3CN (15 mL), DABCO (5 mol%) was
Antitubercular evaluation
Table 5 Antitubercular activity data of heteroaryl-substituted
benzenes
Newly synthesised compounds 4(a–c) and 5(d–f) were
screened for antitubercular activity against M. tuberculosis
H37Rv strain using Lowenstein–Jensen medium method
(Cambau et al., 2000; Jain et al., 2012b, 2013). Ten milli-
gram of each synthesised compound was dissolved in 10 mL
of dimethyl sulphoxide (DMSO) to get a concentration of
1,000 lg/l. Further dilutions were made with DMSO to get
different concentrations such as 100, 10 and 1 lg/mL. 0.8 ml
of each concentration was used for the study. To this, 7.2 ml
of Lowenstein–Jensen medium was added.
Compound
Concentration (lg/mL)
Mycobacterium tuberculosis
100
10
1
Control
??
-ve
-ve
-ve
-ve
-ve
-ve
-ve
??
-ve
-ve
-ve
-ve
-ve
-ve
-ve
??
-ve
-ve
-ve
-ve
-ve
-ve
-ve
Pyrazinamide
4a
4b
4c
5d
5e
5f
Pyrazinamide was used as the standard drug. The dilu-
tion of pyrazinamide was made with DMSO to get different
concentrations of 100, 10 and 1 lg/mL. 0.8 ml of each
concentration was used for the study. A sweep from the M.
tuberculosis H37Rv culture was discharged with the help of
nichrome wire loop with a 3 mm external diameter, into a
‘‘??’’ indicates intensive growth of M. tuberculosis
‘‘-ve’’ indicates complete inhibition of H37Rv
Table 6 Antibacterial activity
Entry
Compound
Escherichia
coli
Salmonella
typhi
Klebsiella
pneumoniae
Pseudomonas
aeruginosa
of heteroaryl-substituted
benzenes (zone of inhibition in
mm)
1
2
3
4
5
6
7
8
Ciprofloxacin
22
??
14
12
17
10
14
10
24
??
24
9
22
??
18
8
23
??
16
10
14
12
18
8
Control
4a
4b
4c
16
14
16
7
12
16
20
9
Minimum inhibitory
concentration is 20 lg/mL
5d
5e
‘‘??’’ indicates no zone of
inhibition
5f
Table 7 Antifungal activity of
heteroaryl-substituted benzenes
(zone of inhibition in mm)
Entry
Compound
Candida
albicans
Candida
tropicalis
Aspergillus
flavus
Aspergillus
niger
1
2
3
4
5
6
7
8
Clotrimazole
20
??
18
24
10
9
21
??
12
21
8
19
??
16
12
14
12
14
9
23
??
20
15
8
Control
4a
4b
4c
Minimum inhibitory
concentration is 20 lg/mL
5d
10
42
8
10
18
10
5e
16
7
‘‘??’’ indicates no zone of
inhibition
5f
123

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Med Chem Res (2014) 23:2608–2614
sterile distilled bijou bottle containing 6 mm glass beads
and 4 mL of sterile distilled water. The bottle was shaken
with the help of a mechanical shaker for 2 min, and then
using nichrome wire loop, 3 mm external diameter, a
loopful of suspension was inoculated on the surface of each
of Lowenstein–Jensen medium containing the test com-
pounds. Lowenstein–Jensen medium containing pyrazina-
mide as well as control were inoculated with M.
tuberculosis H37Rv strain. The inoculated medium was
incubated at 37 °C for 4 weeks. At the end of 4 weeks,
readings were taken and recorded in (Table 6).
1H-NMR (400 MHz, CDCl3): dH 4.86 (s, 1H), 5.69–5.70
(d, 2H), 6.47 (d, 1H), 6.732–6.750 (t, 2H), 7.23–7.39 (m,
6H), 7.26 (s, 1H); 13C NMR (CDCl3, 125 MHz): dC 94.1
(C–CN), 119.2 (CN), 129.2 (Ar–C), 132.1 (C–HetAr),
134.0 (C–NO2), 142.6 (C–NH2) and 148.6 (C–C6H5);
FABMS m/z (% of abundance): 159 (100 %), 227 (58 %),
305 (44 %, M?), 306 (28 %, M??1), and 307 (20 %, M?
?2); C17H12N4O2 (304.30): Calcd. C, 67.10; H, 3.97; N,
18.41; O, 10.52; Found. C, 67.11; H, 3.95; N, 18.43; O,
10.54.
3-Amino-4-nitro-5-(thiophen-2-yl)-[1,10-biphenyl]-2-
Antibacterial evaluation
carbonitrile (4b)
The sensitivity of the bacteria isolated to the test com-
pounds were done by agar-diffusion techniques (Mehta and
Patel, 2006) stock solution at a concentration 10 mg/mL of
each compound was prepared in DMSO. Twenty microlitre
of each of the solution was adsorbed on sterile 6 mm
Whatmann filter paper (#4) discs and kept for few hours
under vacuum to remove the solvent.
White powder, mp. 189–191 °C; IR (KBr) t max/cm-1
:
3408, 3311, 2214, 1558, 1387 cm-1; H-NMR (400 MHz,
CDCl3): dH 5.751 (s, 2H), 7.26 (s, 1H), 7.17–7.33 (m, 6H),
and 7.62–7.90 (m, 3H); 13C NMR (CDCl3, 125 MHz):
dC 93.6 (C–CN), 116.3 (CN), 128.0 (Ar–C), 128.45
(C–HetAr), 132.3 (C–NO2), 141.3 (C–NH2), and 156.4
(C–C6H5); FABMS m/z (% of abundance): 136 (72 %),
155 (63 %), 237 (100 %), 321 (31 %, M?), 322 (20 %,
M??1), and 323 (10 %, M? ?2); C17H11N3O2S (321.35);
Calcd. C, 63.54; H, 3.45; O, 9.96; s, 9.99; N, 13.08; Found.
C, 63.55; H, 3.65; O, 9.96; s, 9.99; N, 13.07.
1
Grown cultures were stored in trypticase soya broth
oxide maintaining the pH 7.3 in 0.5 % agar at 4 °C in the
screw capped tubes. Trypticase soya agar (DIFCO) plates
were inoculated with standard suspension of different
bacterial cultures containing 107 cfu/mL using sterile cot-
ton swabs to obtain a confluent lawn. The prepared discs
were placed on the surface at different positions and plates
were incubated at 37 °C for 24 h. The results were recor-
ded by measuring the zones of inhibition in mm against
each compound (Table 6).
3-Amino-5-(furan-2-yl)-4-nitro-[1,10-biphenyl]-2-
carbonitrile (4c)
Off white powder, mp. 273–275 °C; IR (KBr) tmax/cm-1
:
3407, 3328, 2192, 1560, 1370 cm-1; H-NMR (400 MHz,
CDCl3): dH 5.12 (s, 2H), 7.18–7.23 (q, 3H), and 7.28–7.38
(m, 6H); 13C NMR (CDCl3, 125 MHz): dC 96.3 (C–CN),
114.8 (CN), 129.2 (C–HetAr), 129.4 (Ar–C), 132.1
(C–NO2), 142.6 (C–NH2), and 161.1 (C–C6H5); FABMS
m/z (% of abundance):136 (75 %), 182 (50 %), 227 (100 %),
238 (59 %), 307 (26 %, M?), and 308 (11 %, M??1);
C17H11N3O2S (305.29); Calcd. C, 66.88; H, 3.63; N, 13.76;
O, 15.72; Found. C, 66.87; H, 3.62; N, 13.77; O, 15.73.
1
Antifungal evaluation
The antifungal activity of compounds 4(a–c) and
5(d–f) was studied against four fungal cultures. Saboraud’s
dextrose-agar was seeded with 105 cfu/mL (colony form-
ing units) fungal spore suspension and transferred to pet-
riplates. Twenty microlitre (10 mg/mL) of all compound
solutions were impregnated into discs of 6 mm diameter.
And the discs were kept under vacuum for few hours to
evaporate solvent. Then the discs were placed at different
positions on agar surface. The plates were incubated at
37 °C for 7 days. The results were recorded as zones of
inhibition in mm against each compound (Table 7).
3-Amino-40-methoxy-4-nitro-5-(1H-pyrrol-2-yl)-[1,10-
biphenyl-2-carbonitrile (4d)
Pale brown powder, mp. 226–229 °C; IR (KBr) tmax/cm-1
:
3397, 3328, 2965, 2196, 1661, 1503, 1363 cm-1; 1H-NMR
(400 MHz, CDCl3): dH 3.79 (s, 3H), 4.13 (s, 1H),
4.82–4.85 (t, 2H), 6.82–6.84 (d, 2H), 7.08–7.11 (d, 1H),
and 7.26–7.39 (q, 3H); 13C NMR (CDCl3, 125 MHz): dC
55.2 (OCH3), 97.2 (C–CN), 117.7 (CN), 123.2 (Ar–C),
129.5 (C–HetAr), 134.2 (C–NO2), 137.6 (C–NH2) and
153.3 (C–C6H5); FABMS m/z (% of abundance): 154
(75 %), 169 (70 %), 212 (92 %), 267 (100 %), 335 (38 %,
M?), 336 (22 %, M??1), and 337 (8 %, M??2).
Spectral data
3-Amino-4-nitro-5-(1H-pyrrole-2-yl)-[1,10-biphenyl]-2-
carboxylate (4a)
Pale yellow powder, mp. 211–214 °C; IR (KBr) t max/cm-1
:
;
3397, 3329, 3215, 2196, 1660, 1469, 1363 cm-1
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Med Chem Res (2014) 23:2608–2614
2613
C18H14N4O3 (334.33); Calcd. C, 64.66; H, 4.22; N, 16.76;
O, 14.36; Found. C, 64.65; H, 4.23; N, 16.74; O, 14.38.
(q, 2H), 5.630 (s, 1H), 7.189–7.426 (m, 6H), 7.624–7.904 (m,
3H); 13C NMR (75 MHz, CDCl3): dC (ppm) 14.3 (CH3), 62.0
(–CH2–), 128.0 (Ar–C), 129.2 (C–HetAr), 137.4 (C–NO2),
141.2 (C–NH2), and 169.7 (C=O); C19H16N2O4S (368.41);
Calcd. C, 61.94; H, 4.38; N, 7.60; O, 17.37; S, 8.70; Found.
C, 61.96; H, 4.35; N, 7.62; O, 17.35; S, 8.67.
3-Amino-40-methoxy-4-nitro-5-(thiophen-2-yl)-[1,10-
biphenyl]-2-carbonitrile (4e)
Pale yellow powder, mp. 201–203;IR (KBr) tmax/cm-1: 3370,
1
3115, 2226, 1513, 1420, 1397 cm-1; H-NMR (400 MHz,
Ethyl-3-amino-4-nitro(furan-2-yl)-[1,10-biphenyl]-2-
CDCl3): dH 2.57–2.60 (t, 2H), 3.88 (s, 3H), 7.10–7.13 (m, 5H),
and 7.69–7.88 (m, 3H); 13C NMR (CDCl3, 125 MHz): dC 56.9
(OCH3), 96.6 (C–CN), 112.8 (CN), 124.9 (Ar–C), 127.3
(C–HetAr), 128.7 (C–NO2), 140.4 (C–NH2) and 155.5
(C–C6H5) FABMS m/z (% of abundance): 109 (63 %), 140
(60 %), 243 (100 %), 267 (42 %), 350 (46 %, M?), 351
(38 %, M??1), and 352 (20 %, M??2); C18H13N3O3S
(351.38); Calcd. C, 61.53; H, 3.73; O, 13.66; S, 9.13; N, 11.96;
Found. C, 61.52; H, 3.74; O, 13.67; S, 9.13; N, 11.95.
carboxylate (5c)
Off white powder, mp. 291–293 °C; FT-IR (neat) (mmax/cm-1):
3947, 3828, 3462, 3121, 1747, 1690, 1268, 1119, 714; H
1
NMR (300 MHz, CDCl3): d (ppm) 1.362–1.382 (t, 3H),
4.372–4.392 (q, 2H), 5.230 (s, 1H), 7.180–7.225 (q, 3H),
7.278–7.376 (m, 6H); 13C NMR (75 MHz, CDCl3): dC
(ppm) 14.3 (CH3), 61.2 (–CH2–), 127.5 (Ar–C), 130.2
(C–HetAr), 137.5 (C–NO2), 141.9 (C–NH2), and 168.5
(C=O); C19H16N2O5 (352.34); Calcd. C, 64.77; H, 4.58; N,
7.95; O, 22.79; Found. C, 66.79; H, 4.53; N, 7.98; O, 22.76.
3-Amino-5-(furan-2-yl)-40-methoxy-4-nitro-5-[1,10-
biphenyl]-2-carbonitrile (4f)
Ethyl-3-amino-40-methoxy-4-nitro-5-(1H-pyrrol-2-yl)-
Brownish powder, mp. 243–245 °C; IR (KBr) t max/cm-1
3385, 3317, 3033, 2217, 1492, 1345 cm-1 1H-NMR
:
[1,10-biphenyl-2-carbonitrile (5d)
;
(400 MHz, CDCl3): dH 3.28 (s, 3H), 4.67 (s, 2H), 6.31–6.32
(q, 1H), 6.65–6.68 (t, 2H) and 7.22–7.33 (m, 5H); 13C NMR
(CDCl3, 125 MHz): dC 57.7 (OCH3), 91.1 (C–CN), 114.4
(CN), 126.3 (Ar–C), 127.62 (C–HetAr), 128.3 (C–NO2),
142.3 (C–NH2) and 156.3 (C–C6H5); FABMS m/z (% of
abundance): 123 (39 %), 140 (60 %), 154 (53 %), 230
(60 %), 303 (100 %), 335 (41 %, M?), and 336 (24 %,
M??1); C18H13N3O4 (335.31); Calcd. C, 64.47; H, 3.91; N,
12.53; O, 19.09; Found. C, 64.48; H, 3.90; N, 12.52; O, 19.10.
Pale green powder, mp. 231–233 °C; FT-IR (neat)
(mmax/cm-1): 3402, 3214, 3126, 2942, 1763, 1690, 1276, 1109,
741; H NMR (300 MHz, CDCl3): d (ppm) 1.382–1.422 (t,
3H), 3.762 (s, 3H), 4.360–4.380 (q, 2H), 4.152 (s, 1H), 5.160
(s, 2H), 6.840–6.902 (dd, 2H), 7.108–7.120 (d, 1H),
7.272–7.405 (m, 5H); 13C NMR (75 MHz, CDCl3): dC (ppm)
14.4 (CH3), 55.9 (OCH3), 60.9 (–CH2–), 128.3 (Ar–C), 129.8
(C–HetAr), 137.2 (C–NO2), 142.9 (C–NH2), and 168.3
(C=O); C20H19N3O5 (381.38); Calcd. C, 62.99; H, 5.02; N,
11.02, O, 20.98; Found. C, 62.96; H, 5.05; N, 11.00; O, 20.99.
1
Ethyl-3-amino-4-nitro(1H-pyrrol-2-yl)-[1,10-biphenyl]-2-
carboxylate (5a)
Ethyl-3-amino-40-methoxy-4-nitro-5-(thiophen-2-yl)-[1,10-
biphenyl-2-carbonitrile (5e)
Off white powder, mp. 203–205 °C; FT-IR (neat)
(mmax/cm-1): 3165, 3100, 1754, 1590, 1550, 1524, 1325,
756; 1H NMR (300 MHz, CDCl3): d (ppm) 1.372–1.392 (s,
3H), 4.327–4.347 (d, 2H), 6.1 (s, 2H), 7.124–7.242 (m,
2H), 7.4–7.5 (m, 6H), 8.280 (s, 1H), 9.7 (s, 1H); 13C NMR
(75 MHz, CDCl3): dC (ppm) 14.1 (CH3), 60.6 (–CH2–),
127.7 (Ar–C), 130.6 (C–HetAr), 132.1 (C–NO2), 140.8
(C–NH2), and 168.9 (C=O); C19H17N3O4 (351.36); Calcd.
C, 64.95; H, 4.88; N, 11.96; O, 18.21; Found. C, 64.92; H,
4.89; N, 11.94; O, 18. 20.
Off white powder, mp. 213–215 °C; FT-IR (neat)
(mmax/cm-1): 3429, 3108, 1601, 1498, 1276, 1041, 755,
672; H NMR (300 MHz, CDCl3): d (ppm) 1.360 (t, 3H),
2.621–2.652 (t, 2H), 3.920 (s, 3H), 4.350–4.370 (q, 2H),
7.116–7.143 (m, 5H), 7.712–7.890 (m, 3H); 13C NMR
(75 MHz, CDCl3): dC (ppm) 14.5 (CH3), 56.0 (OCH3),
60.3 (–CH2–), 127.7 (Ar–C), 129.6 (C–HetAr), 137.3
(C–NO2), 142.0 (C–NH2), and 166.2 (C=O); C20H18N2O5S
(398.43); Calcd. C, 60.29; H, 4.55; N, 7.03; O, 20.08; S,
8.05; Found. C, 60.31; H, 4.52; N, 7.05; O, 20.05; S, 8.07.
1
Ethyl-3-amino-4-nitro(thiphen-2-yl)-[1,10-biphenyl]-2-
carboxylate (5b)
Ethyl-3-amino-40-methoxy-4-nitro-5-(furan-2-yl)-[1,10-
biphenyl-2-carbonitrile (5f)
Pale brown powder, mp. 195–197 °C; FT-IR (neat)
(mmax/cm-1): 3429, 3118, 1723, 1675, 1276, 1109, 975, 870,
678; 1H NMR (300 MHz, CDCl3): d (ppm) 1.32 (t, 3H), 4.38
Greenish powder, mp. 257–259 °C; FT-IR (neat)
(mmax/cm-1): 3429, 3214, 3121, 3108, 1723, 1609, 1264,
123

2614
Med Chem Res (2014) 23:2608–2614
1041, 760; 1H NMR (300 MHz, CDCl3): d (ppm)
1.390–1.420 (t, 3H), 3.264 (s, 3H), 4.362–4.392 (q, 2H),
4.68 (s, 2H), 6.315–6.327 (q, 1H), 6.654–6.694 (m, 2H),
7.286–7.383 (m, 5H); 13C NMR (75 MHz, CDCl3): dC
(ppm) 14.6 (CH3), 56.3 (OCH3), 62.1 (–CH2–), 128.4
(Ar–C), 130.8 (C–HetAr), 137.9 (C–NO2), 142.7 (C–NH2),
and 166.2 (C=O); C20H18N2O6 (382.37); Calcd. C, 62.82;
H, 4.74; N, 7.33; O, 25.11; Found. C, 62.84; H, 4.72; N,
7.35; O, 25.09.
Krishna NS, Satish KS (2010) An efficient momo-mode MW
controlled multicomponent synthesis of poly substituted ben-
zenes under solvent free conditions. Ind J Chem 49(B):826–829
Mehta AG, Patel KH (2006) Synthesis and antifungal activity of
azetidinone and thiazolidinone derivatives of 2-amino-6-(2-
naphthaleneyl) thiazolo[3,2-d]thiadiazole. Eur
3:267–273
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Chem
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Conclusion
Jain S, Neelaiah B, Jetti SR, Shah H, Surya PD (2012a) Synthesis,
antitubercular and antifungal activities of heteroaryl substituted
oxiranes derived from Baylis–Hillman adducts. Med Chem Res
21(10):2744–2748
Jain S, Keshwal BS, Rajguru D (2012b) A clean and efficient L-
proline-catalyzed synthesis of polysubstituted benzenes in the
ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate.
J Serb Chem Soc 77(10):1345–1352
In conclusion, we have developed a new and efficient
method for the synthesis of heteroaryl-substituted benzenes
catalysed by DABCO. This provides a new strategy for the
synthesis of heteroaryl-substituted benzenes using ketones
and heteroaryl aldehydes as the starting materials. The
synthesised compounds shown to have good antitubercular,
antibacterial and antifungal activities.
Jain S, Keshwal BS, Rajguru D, Bhagwat VW (2012c) A simple and
clean synthesis of polysubstituted 2,6-dicyanoanilines catalyzed
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pot synthesis of dihydropyrano(c)chromene and pyrano[2,3-d]
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